In 1975, a pentapeptide, methionine enkephalin, was reported by Hughes et al., Nature, 258, 577 (1975). This peptide is found in many areas of the brain where it appears to act as a neurotransmitter or neuromodulator in a central painsuppressant system. This naturally occurring peptide binds stereospecifically to partially purified brain opiate receptor sites. See for example, Bradberry et al., Nature, 260, 793 (1976). It is also highly active in bioassays for opiate activity but exhibits only weak, fleeting analgesic activity when injected directly into the brain of the rat, see for example, Belluzi et al, Nature, 260, 625 (1976).
In order to overcome the lack of in vivo activity, a number of investigators have made numerous modifications in the methionine enkephalin structure, such as substituting the glycine in the 2-position with a D-amino acid, N-methylation of the L-tyrosine, substituting the 4-phenylalanine with, for example, methyl or halo, modifying the C-terminus, etc., to produce enkephalin derivatives of varying properties and potencies.
Kiso, et al., Peptide Chemistry 1981,: 65-70, Protein Research Foundation, Osaka, Japan (1982), disclosed the synthesis and activity of short chain enkephalin-like peptides, among them tripeptide and dipeptide alkylamides such as N-methyltyrosine-(D)-methionine sulfoxide-glycine-methylphenethylamide and tyrosine-(D)-methionine sulfoxide-phenylpropylamide.
Vavrek, et al., Peptides 2, 303, 1981 disclosed analogs of enkephalin, among them the dipeptide tyrosine-D-alanine phenylpropylamide, (Tyr-(D)Ala-PPA).
Hansen, et al., U.S. Pat. No. 4,599,325, which issued July 8, 1986 to the inventors of the present invention, discloses tyrosyl dipeptide amides possessing analgesic activity in mammals.
When compared to the Vavrek, et al. compound, the compounds of this invention have unexpected and surprisingly superior properties. The present invention provides new dipeptide derivatives which show improved potency as analgesic agents by both oral and parenteral routes of administration. Additionally, U.S. Pat. No. 4,316,892 relates to certain methionine enkephalin derivatives useful as analgesic agents.